OBJECTIVE: Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA. DESIGN: Randomized interventional trial. SETTING: University laboratory. SUBJECTS: Swine. INTERVENTIONS: In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups ( n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. MEASUREMENTS AND MAIN RESULTS: Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0–6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups ( p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups ( p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. CONCLUSIONS: In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has been used in patients with refractory out-of-hospital cardiac arrest (OHCA). However, recovery of organ function and survival are potentially impaired due to microvascular coagulation causing a “no-reflow” phenomenon. Hypothesis: Early anticoagulant therapy (argatroban) during CPR and/or thrombolytic therapy (streptokinase) at ECPR onset improves recovery of organ function in an OHCA porcine model. Methods: In a blinded and randomized study, 48 swine (40±5kg) were subjected to 8min of ventricular fibrillation cardiac arrest (CA) followed by 30min of goal directed CPR (gdCPR), and 8h of ECPR (33°C) with heparin anticoagulation during ECPR. Animals (n=12) were randomized to one of 4 groups with 350mg/kg argatroban (Arg) or placebo (20mL NSS) given 12min after CA onset and 1.5 MU streptokinase (STK) or placebo (50mL NSS) given at ECPR initiation: Group 1 (placebo and placebo); Group 2 (Arg and placebo); Group 3 (placebo and STK); and Group 4 (Arg and STK). Recovery of cardiac function measured by a cardiac resuscitablity score (CRS), see Table. Recovery of neurologic function measured by amplitude recovery of cortical somatosensory evoked potentials (cSSEP). Data analysis: Kruskal Wallis and single factor ANOVA tests with ( p <0.05 significant). Results: Average CRS and cSSEP recovery were not significantly different between groups. However, the combined average CRS of the argatroban groups (2&4) was 3.2±2.1 compared to 2.0±1.6 for the groups without it (1&3), p =0.03 single factor ANOVA. Furthermore, more animals in groups 2&4 (n=8) achieved a robust recovery in cSSEP amplitude (≥30% amplitude return) than in groups 1&3 (n=4). Discussion: These results provide evidence that argatroban given early during CPR potentially improves early recovery of cardiac and neurological function in a porcine model of OHCA. However, the impact of these therapies on long term recovery remains to be determined.

Background: The effectiveness of CPR declines over time during prolonged cardiac arrest (CA). Intravascular thrombosis may be a contributing factor. As part of a larger study examining antithrombotic therapy in a porcine model of prolonged CA, the impact of early administration of argatroban on CPR hemodynamics is reported. Hypothesis: Early administration of argatroban during CPR improves the quality of goal-directed CPR (gdCPR). Methods: In a blinded and randomized study, 48 swine (40±5kg) underwent an 8min untreated period of ventricular fibrillation CA followed by a gdCPR protocol for 30min (total arrest time 38min). Manual and mechanical chest compressions with the use of an impedance threshold device (ITD) were introduced to maintain end-tidal CO 2 (Et-CO 2 ) >20mmHg. Argatroban (350mg/kg) or placebo (20mL NSS) were administered to respective groups (n=24 per group) 12mins after initiation of CA. Et-CO 2 , coronary perfusion pressure (CPP), end-diastolic pressure (EDP), and intracranial pressure (ICP) were monitored continuously. Averages were taken over the course of gdCPR for hemodynamic parameters. Arterial blood gases (ABGs) were obtained at the end of gdCPR. Analysis between groups was performed using an unpaired t-test (significance = p <0.05). Results: Average hemodynamic parameters were not statistically different between argatroban vs. placebo groups (Et-CO 2 22.6±6.7 vs. 21.5±5.9 mmHg; EDP 25.6±10.7 vs. 23.7±9.6 mmHg; ICP 25.7±2.0 vs.20.9±2.7 cmH 2 O; CPP 8.7±11.2 vs. 7.0±11.2 mmHg). Final ABG values were also not statistically different between argatroban vs. placebo groups (pH 7.23±0.1 vs. 7.23±0.2; PaO 2 187.4±146.3 vs. 132.2±187.4 mmHg; PaCO 2 38.8±16.6 vs. 43.0±26.1 mmHg; lactate 8.5±1.7 vs. 8.8±1.4 mmol/L). Conclusion: These results demonstrate that early administration of argatroban during CPR did not have a significant effect on gdCPR quality in a porcine model of prolonged CA.

Introduction: The interval from cardiac arrest (CA) to initiation of chest compressions (no-flow time) plays an important role in outcome of CA. The purpose of this study was to evaluate impact of no-flow time on the effectiveness of a goal-direct CPR strategy during prolonged cardiac arrest. Hypothesis: The effectiveness of goal-directed CPR declines with increased no-flow time. Methods: Porcine model of CA was utilized with a period of untreated ventricular fibrillation of 4 or 8 min (groups CA-4, CA-8, n=5/group) followed by a goal-directed CPR protocol for up to 40 minutes. Manual and mechanical chest compressions with impedance threshold device were used sequentially to achieve PetCO2 goal >20 mmHg. Epinephrine infusion and boluses were adjusted with the goal of achieving an arterial diastolic blood pressure >35 mmHg. Hemodynamic parameters were collected throughout the protocol, averaged in 5-minute intervals and compared between groups by an unpaired t-test. Results: A higher average DBP was achieved in the CA-4 vs. CA-8 group during CPR (19 ± 11 mmHg vs. 12 ± 9 mmHg: p<0.04) with stronger responses to epinephrine boluses (max increase 23 vs. 11 mmHg). Brain perfusion through internal carotid artery during CPR relative to baseline averaged 24 ± 34 % vs. 10 ± 12 % in the CA-4 vs. CA-8 group respectively (p<0.006). PetCO2 remained above 20 mmHg 71 ± 35 % vs. 31 ± 13 % of time during CPR in the CA-4 vs. CA-8 group respectively (p<0.001). Conclusion: In this swine model of prolonged VF cardiac arrest, increased no-flow time limits the effectiveness of a goal-directed CPR strategy. Moreover, the response to standard dose of epinephrine was higher after shorter no-flow time.

Background: Extracorporeal CPR (ECPR) is used to provide circulatory stability for organ perfusion and oxygen delivery (DO 2 ) after refractory cardiac arrest (CA). Hemodynamic measurements during ECPR may not necessarily indicate adequate perfusion at the microcirculatory level where DO 2 , oxygen consumption (VO 2 ), and oxygen exchange (O 2 ER) are most critical. In this study, we used sidestream dark-field imaging to measure total vessel density (TVD) to evaluate sublingual microcirculatory flow in a swine model of refractory CA and ECPR. Hypothesis: We hypothesize that TVD can provide real-time assessment of tissue perfusion during post-cardiac arrest ECPR that correlates with traditional measures of tissue oxygenation. Methods: Swine (8) were anesthetized and instrumented for hemodynamic monitoring. Ventricular fibrillation (VF) was induced and CPR initiated after 8min. CPR was administered using a combination of manual and mechanical chest compressions. During CPR the femoral vessels were instrumented for delivery of veno-arterial ECPR. ECPR was initiated 45min after arrest to simulate refractory CA. Sublingual TVD was measured at baseline and after 15min, 1, 2, and 3 hours of ECPR. Results: A one-way ANOVA showed significant difference between baseline TVD: 12.2(2.3)mm -1 and at 3 hours into ECPR: 6.4(3.0)mm -1 (p=0.005). TVD was highly correlated with circuit flow but not with Mean Arterial Pressure (MAP) (r=0.903, p=0.036; r=0.063, p=0.920). In addition, TVD was highly correlated with DO 2 , and lactate, (r= 0.897, p=0.039; r=-0.883, p=0.047) and moderately with VO 2 , O 2 ER, and ScvO 2 (r= 0.776, -0.370, 0.558) respectively. Conclusion: TVD appears to provide a reliable real-time assessment of tissue perfusion during post-cardiac arrest ECPR. The relationships between TVD and MAP, and TVD and flow also suggest that optimization of flow may be more important than optimizing pressure to achieve adequate tissue perfusion during ECPR.